Clinical efficacy of avapritinib in gastrointestinal stromal tumors (GIST) with different <i>KIT</i> genotypes: Post hoc analysis of the phase 1 NAVIGATOR and phase 1/2 CS3007-101 trials.
Authors: Michael C. Heinrich, Jian Li, Xinhua Zhang, Robin L Jones, Suzanne George, Jonathan C. Trent, Cesar Serrano, Yanhong Deng, Sebastian Bauer, Shirong Cai, Xin Wu, Yongjian Zhou, Kaixiong Tao, Zhichao Zheng, Jun Zhang, Yuehong Cui, Hui Cao, Meining Wang, Jin Hu, Lin Shen
Journal: Journal of Clinical Oncology (2023)

11523 Background: Avapritinib, a novel KIT/platelet-derived growth factor receptor α (PDGFRA) kinase inhibitor, is approved in patients (pts) with GIST harboring PDGFRA activation loop (AL) exon 18 mutations, based on unprecedented clinical antitumor activity. Despite available treatments, there remains a great unmet medical need for pts with KIT-AL-mutant GIST receiving 2nd-line (2L) standard of care (SOC) sunitinib, and pts with primary KIT exon 9 ( KIT 9)-mutant GIST receiving 4th-line (4L) SOC ripretinib. This post hoc analysis assessed the clinical benefit of avapritinib in pts with KIT mutations, especially with AL exons 17 and 18, or primary KIT 9 mutations. Methods: Tumor tissue and liquid biopsy samples were collected and analyzed to determine baseline mutational status. KIT molecular subgroups and outcomes were determined in pts with primary KIT mutations treated with oral avapritinib 300 mg once daily (starting dose) enrolled in the phase 1 NAVIGATOR (NCT02508532) and phase 1/2 (China bridging) trials (NCT04254939, CS3007-101). Pts with PDGFRA mutations and PDGFRA- KIT co-mutations were excluded. Progression-free survival (PFS) and objective response rate (ORR) were compared using Cox and logistic regression, respectively. Results: A total of 160 pts with KIT-mutant GIST were evaluated (NAVIGATOR, n= 131; CS3007-101, n= 29). At data cutoff (NAVIGATOR: March 31, 2021; CS3007-101: June 30, 2021), median follow-up duration was 22.0 months (95% CI 18.3–27.4). KIT-AL mutations were more frequently detected (n = 74, 46.3%) than KIT ATP-binding pocket (ABP) mutations (n = 34, 21.3%). Sixty pts (37.5%) had KIT-AL mutations without KIT-ABP mutations (AL pos ABP neg group); the remaining 100 pts were designated as KIT OTHERS. Across all lines of therapy, the adjusted (inverse probability weighting of baseline characteristics) median PFS (mPFS) was longer for the AL pos ABP neg group than for the KIT OTHERS group (9.1 vs 3.4 months; HR 0.47, 95% CI 0.32–0.68; P&lt; 0.0001), and the ORR was higher (31.4% vs 12.1%; odds ratio 3.31, 95% CI 1.44–7.58; P= 0.0047). mPFS and ORR in the KIT AL pos ABP neg group were 19.3 months and 38.5%, respectively, in the 2L setting (n = 13) and 11.0 months and 36.4%, respectively, in Chinese pts (3–9 lines, n = 11). In pts with KIT 9 mutations in the 4L (n = 14) and &gt; 4L settings (n = 19), mPFS was 5.6 and 3.7 months, respectively. Conclusions: This post hoc analysis demonstrated significantly more robust avapritinib antitumor activity in pts with KIT AL pos ABP neg GIST versus pts with other KIT mutation profiles. The results suggest that avapritinib could confer meaningful clinical benefit in pts with GIST and specific KIT mutation types, especially KIT-AL or KIT 9 mutations. Avapritinib might be a potential 2L option for pts with KIT AL pos ABP neg GIST, and in later lines of therapy for pts with AL pos ABP neg or KIT 9 mutation profiles. Clinical trial information: NCT02508532 , NCT04254939 .